Warding Off Disease on Coral Reefs: Antimicrobial Chemical Cues and their Future in Drug Discovery

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Abstract

Unlike many animals, seaweeds do not possess adaptive immune systems to ward off disease.
In many cases, they produce small molecules – natural antibiotics – that prevent colonization or
infection by pathogens. We have found that seaweeds produce unusual secondary metabolites
against pathogen attack, including complex isoprenoid-and shikimate-derived macrolides not
seen in any other organisms. Surprisingly, these natural antifungals are not distributed evenly
across algal surfaces; instead they are concentrated at discrete surface patches where they
provide bursts of protection at sites that may be especially vulnerable to infection due to prior
wounding. Working with the Fernandez lab at Georgia Tech, we applied surface imaging mass
spectrometry to intact algal surfaces to show that antifungal defenses are heterogeneously
distributed, with compound concentrations high enough at localized patches to block infection. This patchy distribution may represent an optimal defense strategy, in which the most vulnerable
parts of the alga are best defended. Chemical defenses of seaweeds also serve as valuable
leads for pharmaceutical development. Members of one group of algal antifungal agents, the
bromophycolides, exhibit potent in vitro and in vivo antimalarial activity with an unexpected
mechanism of action, inhibiting growth of the malarial parasite Plasmodium falciparum at
sub-micromolar concentrations. Using a molecular probe designed from the seaweed’s antifungal
agent, we identified a major molecular target and drug binding mechanism within the malaria
parasite that is helping guide our synthesis of novel analogs for future development.